CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

832

Anti-α4β7 Antibody Facilitates Improved Renal Function During SIV Infection in Macaques Samuel D Johnson 1 , Thomas A. Premeaux 2 , Nageswara Pilli 3 , Jianshi Yu 3 , Lishomwa Ndhlovu 2 , Maureen A. Kane 3 , Siddappa N. Byrareddy 1 1 University of Nebraska Medical Center, Omaha, NE, USA, 2 Weill Cornell Medicine, New York, NY, USA, 3 University of Maryland, Baltimore, MD, USA Background: Combination antiretroviral therapy (cART) reduces the incidence of HIV-associated nephropathy (HIVAN), but people living with HIV (PLWH) remain at high risk for later developing chronic kidney disease (CKD), with a poorly defined etiology. HIV acquisition is associated with reduced plasma all-trans-retinoic acid (atRA) and increased pro-fibrotic galectin (Gal)-3. Clinical trials investigating atRA receptor agonists and Gal-3 antagonists to ameliorate HIVAN/CKD were completed but discontinued after phase 2, necessitating new strategies to restore kidney function. FDA-approved vedolizumab (anti-α4β7) is well-tolerated for inflammatory bowel diseases. Here, we query whether anti α4β7 can improve renal function in a rhesus macaque (RM) infection model. Methods: Nine RMs were CD8-depleted and inoculated with SIVmac251. Daily cART was begun at week two, along with infusions (anti-α4β7 mAb: n=5; IgG controls: n=4) every three weeks until week 23. cART was discontinued (ATI) at week 14. Longitudinal plasma measurements were performed for serum chemistry, retinoids determined by HPLC-UV, and Gal-3 by Luminex. atRA metabolism and podocyte differentiation gene expression were determined by qPCR in kidney samples collected at necropsy and compared to uninfected RMs (n=4). Results: Anti-α4β7 treated RMs had lower measures of urea nitrogen (BUN) and BUN:Creatinine ratio than IgG RMs following therapy and ATI (P=0.0159; P=0.0250), despite comparable measures at baseline. Acute infection was associated with reduced (~35% less) atRA in both groups (P=0.0046; P=0.0014). While atRA remained low in IgG RMs, it increased in anti-α4β7 RMs during cART (P=0.0012) and ATI (P=0.0004), resulting in differences between groups (P=0.0101; P=0.037). atRA precursor retinyl ester (RE) was higher in IgG RMs (P=0.0139) than anti-α4β7 RMs after ATI. RE was positively correlated with BUN:Creatinine (P=0.0152). Anti-α4β7 RMs had greater atRA synthesis (ALDH1A1, ALDH1A3) while IgG RMs had higher atRA catabolism (CYP26A1) gene expression than uninfected RMs. IgG (but not anti-α4β7) RMs also had lower SYNPO and RARRES expression. IgG RMs had lower Gal-3 than anti-α4β7 RMs (P=0.004) after ATI. Gal-3 levels associated negatively with SYNPO expression (P=0.0299) and positively with RE (P=0.0275) and BUN:Creatinine (P=0.044). Conclusion: Our data provide a rationale for repurposing vedolizumab for HIVAN/CKD to restore retinoid signaling, podocyte differentiation, and glomerular filtration thereby improving quality of life in PLWH. Depressive Symptom Burden Predicts Diabetes Mellitus Control Among People Living With HIV Aima A Ahonkhai 1 , Aihua Bian 1 , Paridhi Ranadive 1 , Greer Burkholder 2 , Richard D. Moore 3 , Barbara M. Gripshover 4 , Edward Cachay 5 , Jennifer P. Jain 6 , Kenneth H. Mayer 7 , Deana Agil 8 , April Pettit 9 , Mari Kitahata 10 , Heidi M. Crane 10 , Bryan E. Shepherd 9 , Jessica L. Castilho 1 1 Vanderbilt Univerisity, Nashville, TN, USA, 2 University of Alabama at Birmingham, Birmingham, AL, USA, 3 The Johns Hopkins University School of Medicine, Baltimore, MD, USA, 4 University Hospitals Cleveland Medical Center, Cleveland, OH, USA, 5 University of California San Diego, La Jolla, CA, USA, 6 University of California San Francisco, San Francisco, CA, USA, 7 Fenway Health, Boston, MA, USA, 8 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 9 Vanderbilt Univerisity, Nashville, Tennessee, 10 University of Washington, Seattle, WA, USA Background: Depression is common among people with HIV (PWH) and increases the risk of non-communicable diseases such as diabetes mellitus (DM). Depressive symptoms are associated with poorer medication adherence and adverse HIV outcomes, but less is known about how depression affects DM outcomes. We evaluated the association between depressive symptoms and DM control among PWH and DM. Methods: We examined PWH and DM (defined by HbA1c ≥6.5% or receipt of DM specific medication, or DM related medication and DM diagnosis) cared for at 8 US clinical sites in the CFAR Network of Integrated Clinical Systems (CNICS) cohort from 2005-2023 and who had repeated measures of patient reported depressive symptoms using the Patient Health Questionnaire (PHQ9),. We observed PWH from the date of first HbA1c with a PHQ9 score within 15 months prior and assessed diabetes outcomes using categorical (≤/>7.0%) and continuous HbA1c values. We examined the association between HbA1c and recent depressive symptoms (PHQ9 measured within the 15 months prior to or at the date of HbA1c) using multilevel longitudinal models whereby PWH could

831

Markers of Macrophage Activation and Kidney Function in People With and Without HIV Molly Fisher 1 , David B. Hanna 1 , Anjali Sharma 1 , Todd T. Brown 2 , Michelle Floris-Moore 3 , Frank Palella 4 , Jordan E. Lake 5 , Seble Kassaye 6 , Susan L. Koletar 7 , Eric Seaberg 8 , Igho Ofotokun 9 , Aubri Hickman 10 , Alan Landay 11 , Robert Kaplan 12 , Michael Ross 1 1 Montefiore Medical Center, Bronx, NY, USA, 2 Makerere University–Johns Hopkins University Research Collaboration, Kampala, Uganda, 3 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 4 Northwestern University, Chicago, IL, USA, 5 University of Texas at Houston, Houston, TX, USA, 6 Georgetown University, Washington, DC, USA, 7 The Ohio State University, Columbus, OH, USA, 8 The Johns Hopkins University, Baltimore, MD, USA, 9 Emory University, Atlanta, GA, USA, 10 University of Mississippi Medical Center, Jackson, MS, USA, 11 Rush University, Chicago, IL, USA, 12 Albert Einstein College of Medicine, Bronx, NY, USA Background: HIV infects and activates macrophages, which produce important mediators of inflammation that drive age-related comorbidities. Soluble macrophage activation markers are higher in people with HIV (PWH), even with viral suppression, and have been associated with subclinical cardiovascular disease. Given the close relationship between cardiovascular and kidney disease, we hypothesized these markers would be associated with lower kidney function among PWH. Methods: We performed a cross-sectional study nested within two prospective U.S. multicenter cohorts each of persons with and without HIV; the Women's Interagency HIV Study (WIHS) and for men the Multicenter AIDS Cohort Study (MACS). Serum levels of the macrophage activation markers soluble (s)CD163, sCD14, galectin-3 (Gal-3) and Gal-3 binding protein (Gal-3BP) were measured in 786 (73% PWH) women and 498 (65% PWH) men. Markers were log and Z-score transformed. Multivariable linear regression determined associations of these markers with estimated glomerular filtration rate (eGFR), adjusting for potential confounders including study site, sociodemographics, diabetes, hypertension, hepatitis C, HIV serostatus and tenofovir disoproxil fumarate use. Results: Among 1284 participants, 786 (61%) were women, 902 (70%) were PWH, of whom 486 (54%) were virally suppressed (<50 cp/mL). Median age was lower among women compared to men (40 vs 49 years). sCD14, sCD163 and Gal-3BP levels were significantly higher among PWH versus without HIV (p<0.05). Median eGFR was higher among PWH versus without HIV (95.3 vs 93.6 mL/min in women and 92.7 vs 85.8 mL/min in men). After confounder adjustment, Gal-3 and sCD14 levels were negatively associated with eGFR. Each standard deviation (SD) increase in Gal-3 was associated with a 1.71 mL/ min lower GFR (95% confidence interval -2.66, -0.84; p=0.0004) and each SD increase in sCD14 was associated with a 1.87 mL/min lower GFR (-2.92, -0.82; p=0.0005). These associations were more pronounced among PWH (p for interaction 0.08 and 0.06, respectively). A weak positive association existed between sCD163, and eGFR and no association was observed between Gal-3BP and eGFR. Conclusion: The macrophage markers Gal-3 and sCD14 may have a role in subclinical kidney injury among PWH. Future work will examine macrophage associations with longitudinal kidney outcomes to identify whether they may play a causative role and/or have predictive value for kidney disease risk.

Poster Abstracts

833

CROI 2024 254